Authors :
Pegah Afra, MD – Weill Cornell Medicine; Ryan Verner, PhD – LivaNova; Kristl Vonck, MD, PhD – Professor, Neurology, Ghent University Hospital; William Tatum, DO – Professor, Neurology, Mayo Clinic; Cornelia Drees, MD – Associate Professor, Neurology, Mayo Clinic; Danielle McDermott, MD, MS – Associate Professor, Neurology, University of Colorado Anschutz Medical Campus; Lesley Kaye, MD – Assistant Professor, Neurology, University of Colorado Anschutz Medical Campus; Mesha-Gay Brown, MD – Centura; Amy Keith, BS/BA – Liva Nova; Mei Jiang, PhD – Liva Nova; Zeenat Jaisani, MD – Associate Professor, Neurology, University of Alabama Birmingham; Michael Macken, MD – Associate Professor, Neurology, Northwestern Feinberg School of Medicine; Blake Newman, MD – Assistant Professor, Neurology, University of Utah Health; Rebecca O’Dwyer, MD – Assistant Professor, Neurology, Rush University; Muhammad Zafar, MBBS – Assistant Professor, Pediatrics, Duke University School of Medicine; Selim Benbadis, MD – Professor, Neurology, University of South Florida
Rationale: Since 1997, the VNS stimulation paradigm (SP) has delivered 5-30 Hz pulses in 5 Hz increments. Investigational “Microburst” VNS (µVNS) introduces a new SP by delivering short bursts of high frequency pulses (100 to 300 Hz in 50 Hz increments) separated by brief interburst intervals (0.05-6 seconds). In a pilot study, from 2018 to 2022, µVNS was investigated using parametric measurements of fMRI BOLD response generated by microburst to optimize SP for each subject.
Methods: The
µVNS protocol (LNN001: NCT03446664) was a prospective, interventional, unblinded, multisite study (8 US and 1 international) of VNS therapy system delivering investigational µVNS in two cohorts of
focal onset seizures (FOS) and generalized onset tonic clonic seizures. All subjects had fMRIs at baseline and post-implantation at 0.5, 1, 3, and 6 months to personalize SP in VNS adjustments. Additional VNS adjustment w/o fMRI were done at 9 and 12 months. In FOS cohort, twenty subjects (FOS with or w/o secondary GTC) were enrolled, with COVID-19 pandemic having no effect on achieving goal enrollment. Three months of baseline evaluation were followed by 12 months post VNS implantation. Inclusion criteria were age
≥ 12 years, seizure frequency (SzF) ≥ 3/month, and no seizure free interval > 30 days in the 3 months baseline period. The primary clinical end point was percentage change in SzF/month. Secondary end points were change from baseline in SzF, antiseizure medication (ASM) load, Seizure Severity Questionnaire (SSQ), Columbia suicide severity rating scale (C-SSRS), quality of life in epilepsy (QOLIE-31-P), monitoring for treatment emergent adverse events (TEAEs) and serious adverse events (SAEs).
Results: A total of 20 patients (10 female), 14-61 years of age (mean 31.4/median 27.5) were enrolled in the FOS cohort. Baseline demographics suggest an intractable group with 20 years mean epilepsy duration (median 12.5 years), 10/20 FOS with secondary GTC, 6/20 previous epilepsy surgery. The subjects failed 2-10 ASMs (mean 4.5/median 4). Majority were on ASMs with minimal cognitive side effects (LCM, LTG & LEV). During the trial, personalized SP µVNS was delivered. At 1 year after device implant, 89.5% of patients benefited from µVNS with 57.9% experiencing ≥ 50% reduction in seizure frequency
and 31.6% experiencing ≥ 80% reduction in seizure frequency at 12 months. Mean SSQ improvement surpassed the minimally important change (MIC) threshold for all subdomains. At 12 months, two of QOLIE-31 subscales exceeded the MIC: social functioning and seizure worry. TEAEs were very similar to what is experienced with standard VNS therapy. There was one treatment-related SAE related to premature battery replacement.
Conclusions: Despite sampling limitations and a lack of direct comparison to traditional VNS SP, the 12-month efficacy outcomes demonstrate clinically meaningful reduction in FOS compared to historical data from traditional VNS. Seizure severity and postictal recovery improved without newly identified tolerability concerns. Further studies are needed to determine if this is due to µVNS SP, µVNS personalization with fMRI, or both.
Funding: LivaNova USA Inc.